Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort

Introduction: The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. Conclusions: These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.07.008

Authors: Rafal Dziadziuszko, Tony Mok, Solange Peters, Ji-Youn Han, Jorge Alatorre-Alexander,
Natasha Leighl, Virote Sriuranpong, Maurice Pérol, Gilberto de Castro Junior, Ernest Nadal, Filippo de Marinis, Osvaldo Arén Frontera, Daniel S.W. Tan, Dae Ho Lee, Hye Ryun Kim, Mark Yan, Todd Riehl, Erica Schleifman, Sarah M. Paul, Simonetta Mocci, Rajesh Patel, Zoe June Assaf, David S. Shames, Michael S. Mathisen, Shirish M. Gadgeel

Outcomes According to ALK Status Determined by Central Immunohistochemistry or Fluorescence In Situ Hybridization in Patients With ALK-Positive NSCLC Enrolled in the Phase 3 ALEX Study

Introduction: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study. Conclusions: Outcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.007

Authors: Tony Mok, Solange Peters, Ross Camidge, Johannes Noé, Shirish Gadgeel, Sai-Hong Ignatius Ou, Dong-Wan Kim, Krzysztof Konopa, Emanuela Pozzi, Ting Liu, Isabell R. Loftin, Crystal Williams, Alice T. Shaw

Clinical TrialsKirk SmithFebruary 1, 2021Alectinib, ALK-positive, IHC, FISH, NSCLC

Retrospective Observational Study of ALK-Inhibitor Therapy Sequencing and Outcomes in Patients with ALK-Positive Non-small Cell Lung Cancer

Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors.This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies. READ ARTICLE

Drugs - Real World Outcomes DOI:10.1007/s40801-020-00207-6

Authors: David M. Waterhouse, Janet L. Espirito, Marc D. Chioda, Bismark Baidoo, Jack Mardekian, Nicholas J. Robert, Elizabeth T. Masters

The Relationship Between Primary Tumor Localization and Driver Mutation in Lung Cancer

Driver mutations are detected in 30–35% of metastatic non-small cell lung cancer (NSCLC) patients, andmutation discordance may occur between biopsies. Therefore, false negative results for a driver mutation are reportedin some patients who may need rebiopsy. We aim to determine a clinicopathological feature (especially tumor localization), other than smoking and gender, that predicts driver mutation in metastatic non-squamous NSCLC.Methods: A total of 75 patients with driver mutation reports were included in the study. The age, gender, smokingstatus, pathology, primary tumor location, and mutation of each patient were evaluated. The relationship between theclinicopathological features and driver mutations was analyzed.Results: The median age of the patients was 66 (range: 36–85); 55 (73%) of the patients were male. A driver mutationwas detected in 23 (30.7%) patients. The rates of EGFR, ALK, and ROS1 were 22.7%, 6.7%, and 1.3%, respectively. Drivermutations were more commonly found in ..... READ ARTICLE

EJMO DOI:10.14744/ejmo.2020.13543

Authors: Cengiz Karacin, Tulay Eren, Goksen Inanc Imamoglu, Sema Turker, Fevzi Coskun Sokmen, Mustafa Altinbas

Real-World OutcomesKirk SmithJuly 16, 2020ALK-positive, smoking, non-smoking

Successful alectinib desensitization in a patient with anaplastic lymphoma kinase-positive adenocarcinoma of the lung and alectinib-induced drug rash

Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220918644

Authors: Anderson BE, Luczak TS, Ries LM, Hoefs GE, Silva-Benedict AC.

Case StudyKirk SmithMay 31, 2020Alectinib, desensitization, hypersensitivity, ALK-positive

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues. READ ARTICLE

Lung Cancer. DOI: 10.1016/j.lungcan.2019.11.025

Authors: Kazuhiko Nakagawa, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Koichi Azuma, Young Hak Kim, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Ryo Koyama, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa, Morihiko Hayashi, Wakako Hasegawa, Tomohide Tamura

Clinical TrialsKirk SmithNovember 28, 2019Alectinib, ALK-positive, Crizotinib, J-ALEX, NSCLC, PFS

ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-Positive NSCLC: Pooled Analysis of Two Prospective Trials

Introduction: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. Conclusions: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.10.015

Authors: Johannes Noé, Alex Lovejoy, Sai-Hong Ignatius Ou, Stephanie J. Yaung, Walter Bordogna, Daniel M. Klass, Craig A. Cummings, Alice T. Shaw

Review PaperKirk SmithNovember 8, 2019Alectinib, ALK-positive, NSCLC, Mutation analysis, Resistance

Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial

Background: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. Interpretation: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. READ ARTICLE

The Lancet Respiratory Medicine DOI:10.1016/S2213-2600(19)30252-8

Authors: Yunpeng Yang, Jianya Zhou, Jianying Zhou, Jifeng Feng, Wu Zhuang, Prof Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Prof Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Prof Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Prof Yunpeng Liu, Zhendong Zheng, Prof Gaofeng Li, Prof Ning Wu, Prof Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Prof Li Mao, Giovanni Selvaggi, Xiaobin Yuan, Yuanqing Fu, Tao Wang, Shanshan Xiao, Li Zhang

Patient-reported outcomes from the randomized phase III ALEX study of alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer

Objectives: Alectinib demonstrated superior efficacy and a safety profile that compared favorably with crizotinib in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC) in the phase III ALEX study. We present patient-reported outcomes (PROs) from ALEX to assess disease burden, treatment-related symptom tolerability, and health-related quality of life (HRQoL) with alectinib versus crizotinib. Conclusion: PRO data support the superior efficacy and tolerability of alectinib relative to crizotinib demonstrated in the ALEX study.

READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2019.10.002

AUTHORS: Maurice Pérol, Nick Pavlakis, Evgeny Levchenko, Marco Platania, Julio Oliveira, Silvia Novello, Rita Chiari, Teresa Moran, Emmanuel Mitry, Eveline Nüesch, Ting Liu, Bogdana Balas, Krzysztof Konopa, Solange Peters

Clinical TrialsKirk SmithOctober 11, 2019Alectinib, ALK-positive, Crizotinib, NSCLC, Patient-reported outcomes, ALEX

Refining precision cancer therapy in ALK-positive NSCLC

The treatment approach to advanced anaplastic lymphoma kinase fusion-positive (ALK-positive) non-small cell lung cancer (NSCLC) serves as a paradigm for precision oncology. To date, five ALK-tyrosine kinase inhibitors (TKIs)—crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib—have been approved by the US Food and Drug Administration [1,2]. Although each TKI has significant efficacy in ALK-positive NSCLC, the duration of benefit is invariably limited by the development of acquired resistance... Finally, although not addressed in this study, ALK-independent mechanisms of resistance such as bypass signaling or lineage changes remain a major therapeutic hurdle in ALK-positive NSCLC. In an analysis of 20 lorlatinib-resistant tumour biopsies, 65% did not harbour compound ALK resistance mutations [8], implicating ALK-independent resistance. The prevalence of ALK-independent resistance mechanisms will likely rise as strategies to overcome ALK mutations continue to improve. Thus, eff..... READ ARTICLE

eBioMedicine
DOI:10.1016/j.ebiom.2019.01.059

Authors: Jessica J. Lin and Alice T. Shaw

Review PaperKirk SmithMarch 1, 2019precision cancer therapy, ALK-positive, NSCLC

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non–small-cell lung cancer in Japan

We conducted a large-scale surveillance study as a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non–small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (al..... READ ARTICLE

Cancer Science
DOI:10.1111/cas.13977

Authors: Noriyuki Masuda,Yuichiro Ohe,Akihiko Gemma,Masahiko Kusumoto,Ikuyo Yamada,Tadashi Ishii,Nobuyuki Yamamoto

Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdy405

Authors: S.Gadgeel, S.Peters, T.Mok, A.T.Shaw, D.W.Kim, S.I.Ou, M.Pérol, A.Wrona, S.Novello, R.Rosell, A.Zeaiter, T.Liu, E.Nüesch, B.Balas, D.R.Camidge

Clinical TrialsKirk SmithNovember 1, 2018alectinib, ALK-positive, CNS, non-small cell lung cancer (NSCLC), ALEX